Aradigm's Linhaliq Suffers 'No' For Reducing Time To Exacerbations At US FDA Panel
Executive Summary
Discordant results on Phase III primary endpoint in non-cystic fibrosis bronchiectasis patients troubled advisory committee members, although some suggested they would be more open to approval based upon secondary endpoint data on reduction in exacerbation frequency.
For the second time in two months, discordant pivotal trial results led to a negative US FDA advisory committee review of an inhaled ciprofloxacin formulation to treat non-cystic fibrosis bronchiectasis (NCFB).
In the case of Aradigm Corp.'s Linhaliq (ciprofloxacin dispersion for inhalation), however, some of the panelists suggested they could have seen their way to recommending approval based upon the Phase III secondary endpoint of reduction in exacerbation frequency.
The Antimicrobial Drugs Advisory Committee on Jan. 11 overwhelming concluded that Aradigm had not provided substantial evidence that Linhaliq is effective and safe in delaying the time to first exacerbation. (See box)
Advisory Committee Vote
Has the applicant provided substantial evidence of the safety and efficacy of ciprofloxacin dispersion for inhalation in delaying the time to first exacerbation after starting treatment in non-cystic fibrosis bronchiectasis patients with chronic lung infections with Pseudomonas aeruginosa? Y – 3, N – 12, Abstain - 1
The lone voting question was premised upon the primary endpoint in the Phase III ORBIT trials. Linhaliq demonstrated a statistically significant benefit in delaying the time to first pulmonary exacerbation (PE) in ORBIT-4, with an overall difference in median time of 72 days. However, no benefit on the primary endpoint or any secondary endpoints was shown in ORBIT-3. (Also see "Ciprofloxacin For Bronchiectasis: Can Aradigm Avoid Bayer's Fate At US FDA Panel?" - Pink Sheet, 9 Jan, 2018.)
Panelists generally agreed with Aradigm's assertion that the reduction in the frequency of PEs – a key secondary endpoint – was a more clinically meaningful measure of the drug's efficacy. And on this endpoint, particularly in ORBIT-4, the panelists were more impressed with Linhaliq's effects.
Linhaliq reduced the frequency of all PEs by 37% and severe PEs by 60%, both statistically significant findings, in ORBIT-4. A similar benefit was not seen in ORBIT-3, although the results trended favorably for Linhaliq.
Answering The Question Asked By FDA
The discordant trial results combined with voting question's focus on the Phase III primary endpoint were too much for Aradigm to overcome.
"The question that was asked was quite specific, and I didn’t not feel that that was met," said Jonathan Green, an immunologist at Washington University.
"Does that mean I don’t want this drug to be available? No. I would like my colleagues who treat these patients in the outpatient setting to be able to have a drug such as this available for judicious use for the right subset of patients," such as those with more severe disease, Green said. "I think that there is a role for this. I would like the patients to have it available on label so it can get paid for."
Demetre Daskalakis, acting deputy commissioner in the New City Department of Health and Mental Hygiene's Division of Disease Control, said he voted 'no' on the specific question asked but "the data are a lot more convincing for preventing recurrence, especially in specific populations," such as patients who have more severe illness and more baseline exacerbations.
Jasan Zimmerman, the panel's patient representative, similarly said he voted "no" to the question as posed. "If the question were frequency of pulmonary exacerbations, I would have been closer to 'yes.'"
However, not all "no" votes were conditioned upon the FDA's phrasing of the voting question.
"The data were unconvincing" on delay in time to first exacerbation, said panel chairman Lindsey Baden, director of the infectious disease service at Dana-Farber Cancer Institute. "I think the totality of the evidence, particularly looking at the frequency of the exacerbations, are more convincing although still require I think some more data to support that finding."
'Worth A Shot'
Panelists who voted "yes" also said they were bothered by the discordant results but nevertheless believed Linhaliq should move forward, particularly given the high unmet need for a condition that has no approved treatments.
"I have difficulty with the way the question was posed because I had difficulty with the word 'substantial' and I had difficulty with the primary endpoint. Nevertheless, I think that this would be worth a shot to go forward," said Paula Carvalho, pulmonologist at Boise VA Medical Center. She also suggested the drug's use should be limited to those with moderate to severe disease.
"This is a difficult patient population that is very heterogenous," said Michelle Harkins, a pulmonologist at the University of New Mexico. "It would be nice if the trials were not discordant in their results … but as a pulmonary provider I want to be able to offer something to these patients that would be covered by their insurance."
Two Weeks To Goal Date
FDA will face a quick turnaround time on the Linhaliq application, which has a Jan. 26 user fee deadline.
If the recent panel and agency reviews of Bayer HealthCare Pharmaceuticals AG's ciprofloxacin dry powder inhaler are any predictor, Aradigm appears headed for a complete response letter.
On Nov. 16, the advisory committee recommended against approval of two different regimens of Bayer's drug for NCFB due, in part, to inconsistent Phase III efficacy results. Bayer's studies missed on three of the four primary efficacy measures, and the company unsuccessfully argued that the totality of evidence supported approval. (Also see "Bayer's Inhaled Cipro For Bronchiectasis To Face FDA Panel Efficacy Questions" - Pink Sheet, 14 Nov, 2017.)
Bayer's application received a complete response letter Dec. 29.
Committee members' comments at the Bayer meeting about the need for longer NCFB trials that focus more on exacerbation frequency and antimicrobial resistance, and less on reducing the time to first exacerbation, signaled that Aradigm also could face a difficult panel review. (Also see "Bronchiectasis Trials Should Be Longer, Focus On Exacerbation Frequency" - Pink Sheet, 20 Nov, 2017.)
Exploratory Analyses Don't Explain Away Discordant Results
Seeking to overcome ORBIT-3's failure on its primary endpoint, Aradigm presented various alternative statistical and exploratory analyses aimed at demonstrating that Linhaliq provides a clinically meaningful benefit.
The company also emphasized the importance of the reduction in PE frequency seen with Linhaliq across the Phase III program. While little was known about the natural course of pulmonary exacerbations in NCFB at the beginning of the Phase III trials, recent clinical research has shown that past exacerbations are strong predictors of future events, and clinicians have come to understand that reduction in frequency is the most meaningful endpoint for patients, Aradigm said.
FDA reviewers said that Linhaliq had a "marginal effect" in reducing the time to first PE in ORBIT-4 but they recognized the significant reductions in the frequency of PEs and severe PEs in the study.
However, ORBIT-3 failed to demonstrate any difference between Linhaliq and placebo across all endpoints, and there was no clear explanation for the discordant findings between trials. In addition, slightly more patients on the Linhaliq arm experienced PEs compared to those on placebo in ORBIT-3, FDA reviewers noted.
Statistical reviewer LaRee Tracy said she recognized the importance of reducing exacerbation frequency in NCFB patients.
"I certainly acknowledge the importance of the frequency endpoint," Tracy said. However, Linhaliq is a challenging application "largely because I can't fully understand the discordance between the two trials given the exact designs," she said. "Putting weight on the frequency endpoint I would have expected to have seen something stronger for ORBIT-3 than we saw."
In addition, FDA reviewers raised concerns about the robustness of the ORBIT-4 results in light of an unplanned re-review by Aradigm of the Phase III results after database lock and unblinding. This re-analysis resulted in changes affecting the total number of primary endpoint events and had the effect of making the primary endpoint results of ORBIT-4 statistically significant.
There are concerns regarding the cause and rationale of Aradigm's re-review of the data, and FDA's examination of these changes is ongoing, Tracy said.
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